Synthesis and biological evaluation of potential small moleculeinhibitors of tumor necrosis factor

Papaneophytou, Christos; Alexiou, Panagiotis; Papakyriakou, Athanasios; Ntougkos, Evangelos; Tsiliouka, Katerina; Maranti, Anna; Liepouri, Fotini; Strongilos, A. T.; Mettou, Anthi; Couladouros, Elias A.; Eliopoulos, Elias; Douni, Eleni; Kollias, George; Kontopidis, George

doi:10.1039/c5md00023h

Cited by 13 publications

(20 citation statements)

References 43 publications

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“…The compound SPD- 304 targets TNF directly and has been shown to inhibit activity by destabilising the TNF trimer, resulting in a dimer that is no longer able to interact with receptor 4 . Although this strategy has so far not led to molecules capable of being developed, work is continuing in this area 5–7 . The TNF trimer may also be induced to disassemble by aggregating small molecules 8 .…”

Section: Introductionmentioning

confidence: 99%

Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

et al. 2019

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Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

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Section: Introductionmentioning

confidence: 99%

Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

et al. 2019

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“…The general synthetic routes applied for 16 of the 55 compounds (compounds 5f , 12 , 13 , 14a–d , 15a–c , 16a–17 ) is presented in Supplemental Scheme S1 , whereas the synthesis of the remaining 38 compounds (except for the commercially available SPD304) has been published previously. 10,11 The purity of the tested compounds was determined by analytical high-performance liquid chromatography (HPLC) and was ≥90% for all compounds unless otherwise stated ( Suppl. Table S2 ).…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we designed, synthesized, and biologically evaluated 38 SPD304 analogues. 10,11 Herein, we have designed and synthesized 16 new compounds ( 5f , 12 , 13 , 14a–d , 15a – c , 16a – e , 17 ) and studied the combined total of 55 compounds (i.e., SPD304 and 54 analogues; Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…The design of these 54 analogues focused on eliminating SPD304 toxicity and strengthening the interactions between the inhibitor and the binding site of TNF-α. 10,11…”

Section: Introductionmentioning

confidence: 99%

“…The design of these 54 analogues focused on eliminating SPD304 toxicity and strengthening the interactions between the inhibitor and the binding site of TNF-α. 10,11 A major issue during the evaluation of these compounds was that many exhibited low aqueous solubility. This is always likely when the target site is hydrophobic, as is the case with TNF-α: TNF-α is a typical example of a protein with a shallow ligand-binding site that binds hydrophobic inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Aqueous Solubility Enhancement for Bioassays of Insoluble Inhibitors and QSPR Analysis: A TNF-α Study

et al. 2018

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The aim of this study is to improve the aqueous solubility of a group of compounds without interfering with their bioassay as well as to create a relevant prediction model. A series of 55 potential small-molecule inhibitors of tumor necrosis factor-alpha (TNF-α; SPD304 and 54 analogues), many of which cannot be bioassayed because of their poor solubility, was used for this purpose. The solubility of many of the compounds was sufficiently improved to allow measurement of their respective dissociation constants (K). Parameters such as dissolution time, initial state of the solute (solid/liquid), co-solvent addition (DMSO and PEG3350), and sample filtration were evaluated. Except for filtration, the remaining parameters affected aqueous solubility, and a solubilization protocol was established according to these. The aqueous solubility of the 55 compounds in 5% DMSO was measured with this protocol, and a predictive quantitative structure property relationship model was developed and fully validated based on these data. This classification model separates the insoluble from the soluble compounds and predicts the solubility of potential small-molecule inhibitors of TNF-α in aqueous solution (containing 5% DMSO as co-solvent) with an accuracy of 81.2%. The domain of applicability of the model indicates the type of compounds for which estimation of aqueous solubility can be confidently predicted.

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Synthesis of 3-(N-arylcarbamoyl)chromones from 2-hydroxyarylaminoenones and isocyanates

et al. 2019

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Synthesis and biological evaluation of potential small moleculeinhibitors of tumor necrosis factor

Abstract: A series of 39 novel SPD-304 analogs were designed synthesized and evaluated as inhibitors of TNF.

Cited by 13 publications

References 43 publications

Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

Aqueous Solubility Enhancement for Bioassays of Insoluble Inhibitors and QSPR Analysis: A TNF-α Study

Synthesis of 3-(N-arylcarbamoyl)chromones from 2-hydroxyarylaminoenones and isocyanates

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